International Immunology, Vol. 16, No. 2, pp. 283-293,
February 2004
© 2004 Japanese Society for Immunology
Analysis of autoreactive T cells associated with murine collagen-induced arthritis using peptide–MHC multimers
1 Center for Immunology, University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Boulevard, Dallas, TX 75390-9093, USA 2 Section of Medical Inflammation Research, BMC, Lund University, 22184 Lund, Sweden 3 Seccion de Inmunologia, Hospital Universitario Virgen de la Arrixaca, El Palmar, 30210 Murcia, Spain
Correspondence to: E. S. Ward; E-mail: Sally.Ward{at}Utsouthwestern.edu
Transmitting editor: M. Feldmann
CD4+ T cells that recognize residues 256–270 of type II collagen (CII) associated with the I-Aq (Aq) molecule play a central role in disease pathogenesis in murine collagen-induced arthritis (CIA). Disease is most efficiently induced by immunization with heterologous CII, which elicits heterologous, e.g. bovine, CII256–270:I-Aq-specific T cells that only poorly cross-react with mouse CII. The self-epitope differs from heterologous CII256–270 by a conservative change of glutamic acid (heterologous) to aspartic acid (mouse) at position 266 which confers a lower affinity for binding to the I-Aq molecule. To date, characterization of the nature of T cell recognition in this model has been hindered by the lack of suitable, labeled multimeric peptide–MHC class II complexes. Here, we describe the biochemical properties of both recombinant bovine CII256–270:I-Aq (bCII256–270:I-Aq) and mouse CII256–270:I-Aq (mCII256–270:I-Aq) complexes, and use these as fluorescently labeled multimers (tetramers) to characterize the specificity of CII-reactive T cells. Our analyses show that an unexpectedly high percentage of bCII256–270:I-Aq-specific T cells are cross-reactive with mCII256–270:I-Aq. Interestingly, one T cell clone which has a relatively high avidity for binding to self-CII256–270:I-Aq shows a marked increase in binding avidity at physiological temperature, indicating that this TCR has unusual thermodynamic properties. Taken together, our analyses suggest that the low affinity of mCII256–270 for I-Aq may lead to a state of ignorance which can be overcome by priming CII-specific T cells with heterologous CII. This has relevance to understanding the mechanism by which CIA is induced and provides an explanation for the low arthritogenicity of mouse CII.
Keywords: autoimmunity, MHC, rheumatoid arthritis, T lymphocyte, TCR
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